Abstract / Project Summary Scleroderma (Systemic Sclerosis; SSc) is an autoimmune disease of unknown etiology that is characterized by vascular dysfunction, fibrosis, and inflammation. One in three patients dies within 10 years of diagnosis giving SSc the highest case fatality rate of any systemic autoimmune disease. A lack of biologically-relevant, human SSc disease models has created a critical unmet need for more efficient preclinical drug screening models that can provide faster, more cost-effective ways of predicting the success or failure of drugs designed to treat SSc. Recent advances in tissue engineering have resulted in 3D skin tissue-based disease models that can provide in vitro models of SSc that closely mimic this disease in humans. This will shorten the preclinical drug development timeline, save animal lives, reduce drug failure rates, and inform FDA decision-making for the development of new and effective disease therapeutics. The development of 3D skin-like tissue models that accurately recapitulate the SSc phenotype will be an important advancement over currently available monolayer, 2D tissue cultures. Bringing 3D skin models into Celdara Medical allows us to pair this promising in vitro system with our existing portfolio of SSc diagnostics and SSc, fibrosis and cancer drug development efforts. Beyond our immediate goals, of optimizing and exploiting these well-established 3D skin-like tissues models for drug screening will advance complex tissue models for other organ systems, such as lung. By using multiple, patient-derived cell types we will optimize 3D tissues to establish proof-of-concept that robust, SSc- specific, 3D tissue models can serve as preclinical drug screening platforms for new therapeutic agents for SSc. Our aims are (1) to optimize fabrication of SSc-specific 3D tissue models harboring primary SSc-derived fibroblasts, macrophages (Ms) and keratinocytes, and (2) To analyze the cell biology, tissue properties and genomic similarity of 3D skin-like tissues made from SSc cells against SSc patient skin biopsies.